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Staphylococcus aureusis a major cause of severe pulmonary infections. The evolution of multi-drug resistant strains limits antibiotic treatment options. To date, all candidate vaccines tested have failed, highlighting the need for an increased understanding of the immunological requirements for effective S. aureusimmunity. Using an S. aureusstrain engineered to express a trackable CD4+T cell epitope and a murine model of S. aureuspneumonia, we show strategies that lodge Th1 polarised bacterium specific CD4+tissue resident memory T cells (Trm) in the lung can significantly attenuate the severity of S. aureuspneumonia. This contrasts natural infection of mice that fails to lodge CD4+Trm cells along the respiratory tract or provide protection against re-infection, despite initially generating Th17 bacterium specific CD4+T cell responses. Interestingly, lack of CD4+Trm formation after natural infection in mice appears to be reflected in humans, where the frequency of S. aureusreactive CD4+Trm cells in lung tissue is also low. Our findings reveal the protective capacity of S. aureusspecific respiratory tract CD4+Th1 polarised Trm cells and highlight the potential for targeting these cells in vaccines that aim to prevent the development of S. aureuspneumonia.

Tissue-resident memory T cells (Trm) in the lung provide a frontline defence against respiratory pathogens. Vaccination models that lodge CD8+Trm populations in the lung have been developed, all of which incorporate the local delivery of antigen plus adjuvant into the airways; a necessary approach as local cognate antigen recognition is required for optimal lung Trm development. Although pulmonary delivery of antigen is important for lung Trm development, the impact the co-administered adjuvant has on Trm differentiation is unclear. We show that while altering the adjuvant co-administered with the pulmonary delivered antigen does not impact the size of the lung Trm population, a particular adjuvant, zymosan, when administered into the airways without antigen can drive effector CD8+T cells to differentiate into lung Trm. Zymosan signalling via dectin-1 receptor was sufficient to promote antigen-independent lung Trm development. When combined with an injectable influenza vaccination regime, intranasal zymosan delivery significantly boosted the size of the influenza virus-specific lung Trm population. Our results highlight that eliciting the appropriate local inflammatory milieu can by-pass the requirement for local antigen recognition in lung Trm development and emphasises that the appropriate selection of adjuvant can greatly improve vaccines that aim to elicit pulmonary Trm.